Neural cell adhesion molecules (CAMs) of the immunoglobulin superfamily nucleate and maintain groups of cells at key sites during early development and in the adult. In addition to their adhesive properties, CAMs homophylic and heterophylic interactions can affect intracellular signaling. Their ability to influence developmental events, including cell migration, proliferation, and differentiation may therefore result both from their adhesive as well as their signaling properties.
The neural cell adhesion molecule, NCAM, was the first discovered neural CAM. Since the discovery NCAM has been intensively studied and now it is well characterised.
NCAM belongs to the immunoglobulin (Ig) superfamily. Its extracellular part consists of five Ig-like and two fibronectin type III (F3) modules (Berezin et al., 2000). NCAM assists both the cell-cell and cell-substratum interactions. NCAM binds to various extracellular matrix components such as heparin/heparan sulfate, chondroitin sulfate proteoglycans, and different types of collagen. Cell-cell interactions are mostly assisted by the NCAM homophilic interaction.
The different modules of NCAM have been shown to perform distinct functions. Thus, NCAM homophilic binding is believed now to depend on the first three Ig modules. The heparin binding sequence is localized to the Ig2 module. NCAM also binds to the neural cell adhesion molecule L1. This interaction is believed to take place between the fourth Ig module of NCAM and an oligomannosidic moiety expressed on L1. The two membrane-proximal F3 modules of NCAM has been suggested to be involved in FGFR binding. Among a number of ligands of NCAM the most intriguing remain to be ATP. NCAM has been demonstrated to hydrolyze extracellularly adenosine triphosphate (ATP) (Dzhandzhugazyan and Bock, 1993 and 1997), and the proximal F3 modules have been suggested to be involved in this activity of NCAM. Recently, ATP has been demonstrated to be a modulator of NCAM induced neuritogenesis (Skladchikova et al., 1999). However, the role extracellular ATP, which is one of the most abundant neurotransmitters in the brain, in relation to known biological functions of NCAM is not well understood.
A number of research groups has now accumulated a large body of evidence indicating that intracellular signaling cascades underlying the NCAM-mediated axonal outgrowth are similar to signal transduction cascades which are activated due to stimulation of the fibtoblast growth factor receptor (FGFR).
Fibroblast growth factor receptors (FGFRs) are a family of four closely related receptor protein tyrosine kinases consisting extracellularly of three Ig-like modules and intracellularly of a split tyrosine-kinase module (Powers et al., 2000). The receptors are known as key regulators of morphogenesis, development, angiogenesis, and wound healing. FGFR activation and signaling are dependent on dimerization of the receptor which is induced by a high affinity binding of its ligand, fibroblast growth factor (FGF), and it also requires participation of cell surface heparin or heparan sulphate proteoglycans.
The major neural CAMs, NCAM, L1 and N-cadherin, all have been regarded as a new class of putative alternative ligands of FGFR, although there have not been so far obtained any evidence for a direct interaction between these CAMs and the receptor so far. The identification of a common structural motif which might be a prerequisite for the interaction with FGFR seems to be very advantageous in view of the development of new drugs for the treatment of a variety of pathologic disorders where the regulation of activity of FGFR may play the key role.